Tau inclusions in neurons and glia are signature lesions of tauopathies. Alzheimer's disease (AD), the most common tauopathy, is characterized by neurofibrillary tangles (NFTs) composed of filamentous hyperphosphorylated tau and Abeta-rich senile plaques (SPs). In contrast, sporadic and hereditary tauopathies are characterized by filamentous tau inclusions in neurons and/or glia with few/no SPs or other diagnostic lesions. Familial tauopathies known as frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17) are caused by >30 different tau gene mutations in >50 kindreds that induce disease due to losses of tau functions, gains of toxic functions or aberrant tau mRNA splicing. These and other insights into brain degeneration linked to tau abnormalities in the last 5 years make it timely to determine if disease pathways causing tauopathies represent "drugable" targets for therapeutic interventions in AD and FTD tauopathies. For example, since aberrant tau phosphorylation and disruption of microtubules (MTs) are linked to impaired axonal transport and brain degeneration, preventing tau phosphorylation and MT depolymerization are attractive targets for developing novel therapies for tauopathies. Thus, Project 4 will test the hypothesis that abnormal tau phosphorylation plays a mechanistic role in the pathogenesis of tauopathies and evaluate potential "drugable" targets in tau mediated brain degeneration for proof-of-concept animal model studies for the development of novel therapies for tauopathies.